Derivatives of the 2-(lower alkyl)-3(lower alkyl)-4-phenyl-3-or 4-cyclohexenecarboxylic acids

ABSTRACT

COMPOUNDS OF THE GENERAL FORMULA   1-(R&#39;&#39;O-CO-),2-R&#34;,3-R&#34;&#39;&#39;,4-PHENYL-CYCLOHEX-3OR4-ENE   ARE DISCLOSED WHEREIN R&#39;&#39;&#39;&#39; AND R&#39;&#39;&#39;&#39;&#39;&#39; ARE SELECTED FROM THE GROUP CONSISTING OF LOWER ALKYL OF UP TO 3 CARBON ATOMS; AND R&#39;&#39; IS SELECTED FROM THE GROUP CONSISTING OF SECONDARY ALKYL OF FROM 9 TO 20 CARBON ATOMS, ALKENYL OF FROM 3 TO 20 CARBON ATOMS; 1-ADAMANTLY, 2-ADAMANTLY, CYCLOPENTYL; AND THE DOTTED LINES REPRESENT A DOUBLE BOND AT EITHER THE 3- OR THE 4-POSITION. THESE COMPOUNDS ARE ACTIVE SUPPRESSANTS OF REPRODUCTION IN LOW DOSES WHEN ADMINITERED ORALLY OR PARENTERALLY. WHEN GIVEN IN A SINGLE SUBCURTANEOUS AND OR ORAL DOSE SOME OF THESE COMPOUNDS HAVE LONG ACTING EFFECTS IN THE SUPPRESSION OF ANIMAL REPRODUCTION.

United States Patent 0 US. Cl. 260469 3 Claims ABSTRACT OF THE DISCLOSURE Compounds of the general formula III R!) are disclosed wherein R" and R' are selected from the group consisting of lower alkyl of up to 3 carbon atoms; and R is selected from the group consisting of secondary alkyl of from 9 to 20 carbon atoms, alkenyl of from 3 to 20 carbon atoms, l-adamantyl, Z-adamantyl, cyclopentyl; and the dotted lines represent a double bond at either the 3- or the 4-position. These compounds are active suppressants of reproduction in low doses when administered orally or parenterally. When given in a single subcutaneous and/or oral dose, some of these compounds have long acting effects in the suppression of animal reproduction.

This application is a continuation-in-part of my application Ser. No. 763,026, filed Sept. 26, 1968, now Pat. No. 3,629,269.

The present invention relates to compounds of the general formula wherein R" and R" are selected from the group consisting of lower alkyl of up to 3 carbon atoms; and R is selected from the group consisting of secondary alkyl of from 9 to 20 carbon atoms, alkenyl of from 3 to 20 carbon atoms, l-adamantyl, 2-adamantyl,cyclopentyl; and the dotted lines represent a double bond at either the 3- or the 4-position.

The compounds of the present invention are related to the compounds disclosed in US. Pat. 3,344,147 and in my oopending patent applications Ser. Nos. 662,310, now Pat. No. 3,591,624; 747,075, now abandoned; 622,295, now Pat. No. 3,567,770; 723,614, now abandoned; and 728,900, now Pat. No. 3,557,129. The compounds of the present invention are active suppressants of reproduction in low doses upon oral or parenteral administration. Some of the compounds of the present invention, when given in one subcutaneous injection or in one oral dose, suppress reproduction over a long period of time.

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These compounds are all esters of 2-(lower alkyl)-3- (lower alkyl)-4-phenylcyclohexenecarboxylic acid and analogs of the same and therefore may be prepared by the formation of the acid halide of the cyclohexenyl carboxylic acid (by means of reaction with thionyl chloride or phosphorus halides) followed by reaction with an alcohol of the formula ROH. Alternatively, the appropriate metal salt of the cyclohexenyl acid may be reacted with a compound of the formula R'-(halide), for example with u-glyceryl monochlorohydrin, or with an alkylsulfonate of the formula R'OSO R". A further method consists of preparing the anhydride of the cyclohexenyl acid (for instance, by reacting with acetic anhydride) and condensing the product with a hydroxylic reagent of the formula ROH.

Furthermore, the anhydride of a 4-hydroxy-4-arylcyclohexanecarboxylic acid may first be prepared after which it is condensed with the appropriate alcohol of the formula R'OH and the resultant ester subsequently dehydrated in the presence of a Lewis acid in order to prepare the corresponding cyclohexenyl carboxylic acid ester. Said dehydration step is preferably eflfected with hot glacial acetic acid and paratoluenesulfonic acid. This particular reaction sequence is illustrated as follows:

HO CO R HO E- O Q The present compounds may also be prepared by acid catalysed esterification between the cyclohexenyl carboxylic acid and an alcohol of the formula ROH; transesterification, in which the RO-group of the ester is replaced with another R-O group under basic catalysis; or by the reaction of the cyclohexenyl carboxylic acid with a diazoalkane or an olefin. The latter two processes may be generally illustrated as follows:

In the above formulae, R R R and R represent hydrogen or a wide range of substituents such as alkyl, alkenyl and substituted alkyl or alkenyl.

The following examples illustrate the preparation of some of the compounds of the invention. While only one method of preparation is disclosed for each compound, it is to be understood that a number of the other methods noted above can also be utilized.

In said examples, reference to the drying of organic solutions implies the use of anhydrous magnesium sulfate or sodium sulfate, evaporation is invariably performed under vacuum (most conveniently that obtained with a waterpump aspirator), filtration is with suction, temperatures are degrees Centigrade, and melting points are corrected.

Infrared spectra (neat for oils, KBr pellets for solids) were taken on a Beckman I R5 spectrophotometer and proton magnetic resonance (NMR) spectra on a Varian A-60 instrument. NMR spectral data are given as chemical shift values, 8, in p.p.m. The 6 values given in the following examples are those assignable, where possible, to a vinyl proton on the cyclohexene ring and to the 2- methyl and 3-ethyl groups.

ESTERS FROM A SODIUM CARBOXYLATE AND A HALIDE Example 1.B,'y-Dihydroxypropy1 2-Methyl-3-ethyl-4- phenyl-4-cyclohexenecarboxylate A solution of 2.0 g. of 2 methyl 3 ethyl 4 phenyl- 4-cyclohexenecarboxylic acid reported in U.S. Pat. No. 3,344,147 and 0.5 g. of sodium hydroxide in 25 ml. of methanol plus 60 ml. of dimethylformamide is evaporated to a volume of 40 m1. and to the resulting slurry is added 4 ml. of a-glyceryl monochlorohydrin. This mixture is heated at 100 for 2 /2 hours and then it is evaporated to remove dimethylformamide. The residue is shaken with ether and water and then the ether phase is washed twice with cold 5% sodium hydroxide and four times with water. Evaporation of the dried ether solution leaves a viscous oil which slowly crystallizes. Recrystallization from ether-hexane affords 1.30 g. of fine white flakes, m.p. 72-73 Mmax: 2.89, 5.81,

14.20,u(KB,)

NMR (CDCL 0.80, 0.85, 0.92, 1.01; 5.65.

Calcd. for C H C, 71.67; H, 8.23. Found: C, 71.78;

ESTERS FROM ACID CHLORIDE AND AN ALCOHOL Example 2.-1-Adamantyl 2-Methyl-3-ethyl-4-phenyl-4- cyclohexenecarboxylate A mixture of 3.0 g. of 2-methyl-3-ethyl-4-phenyl-4- cyclohexenecarboxylic acid and 15 ml. of thionyl chloride is refluxed for fifteen minutes and then the yellow solution is evaporated and the residual oil is distilled to afford 3.0 g. of the acid chloride, a mobile yellow oil which boils at 100-102/.02 mm. and has 21 1.5527 and Mmax. 5.57, 9.98, 11.63, 12.35, 13.10-13.40, 14.28;; (neat).

The distilled acid chloride is added to a chilled (-10"), vigorously stirred solution of 1% molecular equivalent of l-hydroxyadamantane in 20 ml. of dry pyridine. This reaction mixture is stirred at 25 for 15 minutes and then heated at 90-95 for 1.5 minutes. Then it is cooled and 5 ml. of water is added and the mixture is stirred vigorously for 2 hours. After dilution with 150 ml. of ether, the ether phase is washed twice with cold 5% hydrochloric acid to remove pyridine, then twice with cold 5% sodium hydroxide and then the ether solution is dried and evaporated. The residual oil is developed on a column of alumina (neutral, W-1) prepared in benezene-hexane. Elution with benzene and ether affords the ester free of alcohol and carboxylic acid. A crystalline ester is recrystallized from methanol, and an oily ester is distilled under high vacuum to afford the following purified product. 1- Adamantyl 2 Methyl 3 ethyl 4 phenyl 4 cyclohexenecarboxylate; m.p. 94-95".

Mmax: 5.81, 8.22, 8.49, 9.42, 10.23, 13.14, 14.2011.

(KBr).

NMR (CDCl;.;): 0.77, 0.83, 0.88, 5.63.

Calcd. for C H O C, 82.49; H, 9.05. Found: C, 82.32;

Example 3.-Benzhydryl 2-Methyl-3-ethyl-4-phenyl-4- cyclohexenecarboxylate This compound is prepared following the procedure of Example 2, and using benzhydrol in the place of l-hydroxyadamantane.

The compound is a viscous yellow oil of b.pt. 190- 200/.001 mm.;

Mmax: 5.79, 8.63, 10.07, 11.80, 13.20, 14.26;; (neat).

NMR (CHCI 0.70, 0.81, 0.89, 5.65.

Calcd. for C H O C, 84.84; H, 7.37. Found: C, 85.05;

Example 4.-Cycl0pentyl 2-Methyl-3-ethyl-4-phenyl-4- cyclohexenecarboxylate This compound is prepared following the procedure of Example 2, and using cyclopentanol in the place of 1- hydroxyadamantane.

Distillation (without prior chromatography) gives an oil, b.p. 125130/0.001 mm. This solidifies and is recrystallized from methanol to give white flakes, m.p. 58-59. Yield: 75%.

Mmax: 5.81, 8.29, 8.64, 11.90, 13.25, 14.23,u(KBr). Em-

pirical Formula: C H O Anal.Calcd.: C, 80.73; H, 9.03. Found: C, 80.81; H,

Example 5.Decy1 2-Methyl-3-ethyl-4-phenyl4- cyclohexenecarboxylate This compound is prepared following the procedure of Example 2, and using n-decyl alcohol in the place of 1- hydroxyadamantane.

Chromatography, followed by distillation (b.p. 175- l at .001 mm.) affords the decyl ester as a very pale yellow, mobile oil.

Mmax: 5.78, 8.29, 8.60, 11.88, 13.22, 1427a.

Empirical Formula: C H O Calcd.: C, 81.20; H, 10.48. Found: C, 80.78; 80.75; H,

Example 6.--(2-Methyl-3-ethyl-4-phenyl-4-cyclohexenyl- 1) methyl 2 Methyl-3-ethyl-4-phenyl-4-cyclohexenecarboxylate To a stirred solution of 2.9 g. of (2-methyl-3-ethyl-4- phenyl 4 cyclohexenyl 1)methanol (prepared as described in US. Pat. No. 3,344,147) in 12 ml. of pyridine is added 3 g. of distilled Z-methyl-3-ethyl-4-phenyl-4-cyclohexenecar-bonyl chloride (prepared as described in Example 2). This mixture is heated at -95 for twenty minutes and then ice and ether are added. The mixture is shaken and then separated. The ether solution is washed twice with cold dilute hydrochloric acid and then with water and dilute sodium hydroxide. The residue obtained from drying and evaporation of the ether solution is triturated with pentane and stored at 0 to afford 2.4 g. of a crystalline solid ester which is recrystallized from ether and from acetone to alford 1.65 g. of (2-methyl-3-ethyl- 4 phenyl 4-cycl0hexenyl-1)methyl 2-methyl-3-ethyl-4- phenyl 4 cyclohexenecarboxylate, White granules of m.p. 153156.

Mmax: 5.77, 8.23, 8.43, 8.51, 9.94, 11.80, 13.14, 14.12,

l4.22,u(KBr).

Empirical Formula: C H O Calcd.: C 84.16; H, 8.83. Found: C, 84.05; H, 8.88.

Example 7.2-Adamantyl 2-Methyl-3-ethyl-4-phenyl-4- cyclohexenecarboxylate 3.0 g. of 2 methyl 3-ethyl-4-phenyl-4-cyclohexenecarboxylic acid is converted to the acid chloride as described in Example 2. The distilled acid chloride is added to a solution of 2-hydroxyadamantane in ml. of dry pyridine. This reaction mixture is maintained at 25 for 10 minutes and then it is heated at 90-95 for 10 minutes. Six drops of water are added and heating is continued for 5 minutes longer. After cooling, the reaction mixture is diluted with ether and then it is washed with dilute hydrochloric acid, water, and dilute potassium carbonate. Drying and evaporation of the ether solution affords a viscous yellow oil which is developed on a chromatographic column of neutral alumina. Elution with benzene-ether affords the ester as a colorless oil which slowly solidifies. This is recrystallized twice from hexane to afford 1.8 g. of 2 adamantyl 2-methyl-3-ethyl-4-phenyl-4-cyclohexenecarboxylate, fine white prisms which melt at 83-84.

)Qmax: 5.78, 8.25, 8.54, 9.91, 13.04, 13.23, l4.20,u.(KBr). Empirical Formula: C H O Calcd.: C, 82.49; H, 9.05. Found: C, 82.57; H, 8.95.

Example 8.1-Adamantylmethyl 2-Methyl-3-ethyl-4- phenyl-4-cyclohexenecarboxylate 3.0 g. of 2 Methyl-3-ethyl-4-phenyl-4-cyclohexenecarboxylic acid is converted to the acid chloride as de scribed in Example 2. The distilled acid chloride is then reacted with 2.0 g. of l-adamantylmethanol in pyridine as described for Example 7. The working up and chromatography are as for the compound of Example 7 and there is thus obtained 2.8 g. of 1 adamantylmethyl 2 methyl-3- ethyl 4 phenyl-4-cyclohexenecarboxylate, a very viscous oil which is freed of solvent under high vacuum. This ester may be distilled at 180190/.001 mm., but this causes partial decomposition and is not a useful method of purification.

Mmax: 5.79, 6.90, 8.28, 8.60, 9.90, 11.88, 13.20, 1428 Empirical Formula: C2'1H36O2- Calcd.: C, 82.60; H, 9.24. Found: C, 82.87; H, 9.23.

Example 9.Benzyl 2-Methyl-3-ethyl-4-pheny1-4- cyclohexenecarboxylate This ester is prepared from the cyclohexenyl acid chloride and benzyl alcohol, following the procedure of Example 2. Chromatography, followed by distillation (b. pt. 170173 at 0.001 mm.) affords the benzyl ester as a colorless oil.

Mmax: 5.79, 8.30, 8.63, 9.95, 11.85, 13.28, 14.30;. Empirical Formula: C H O Calcd.: C, 82.59; H, 7.84. Found: C, 82.79; H, 7.88.

Example 10.-2-Nonadecyl 2-Methyl-3-ethyl-4-phenyl-4- cyclohexenecarboxylate This ester is prepared from the cyclohexenyl acid chloride and 2-nonadecanol, following the procedure of Example 2. Chromatography on alumina affords the crude ester free of the fatty alcohol, and distillation gives the ester as a yellow oil of b.pt. 230235/ 0.001 mm.

Mmax: 5.78, 8.27, 8.58, 11.87, 13.20, 14.28 Empirical Formula: C H O Calcd.: C, 82.29; H, 11.45. Found: C, 82.19; H, 11.71. Example 11.-2-Methyl-2-butenyl 2-Methyl-3-ethyl-4- phenyl-3-cyclohexenecarboxylate This ester is prepared from the cyclohexenyl acid chloride and 2,3-dimethylallyl alcohol, following the procedure of Example 2. Chromatography on alumina affords crude ester and distillation gives the desired ester as a colorless oil of b. pt. 125-130 at .001 mm.

Mmax; 5.78, 8.64, 10.00, 12.04, 13.13, 1427 Empirical Formula: C H O Calcd.: C, 80.73; H, 9.03. Found: C, 80.57; H, 8.89.

6 Example 12.2-Methyl-2-hutenyl 2-Methyl-3-ethyl-4 phenyl-4-cyclohexenecarboxylate This ester is prepared from the A -cyclohexenyl acid chloride and 2,3-dimethylallyl alcohol, following the procedure of Example 2. Chromatography on alumina affords crude ester and distillation gives the desired ester as a colorless oil of b. pt. 140/.001 mm.

Mmax; 5.78, 8.29, 8.63, 10.04, 11.89, 12.06, 13.27,

Empirical Formula: C H O =312.4.

Anal.Calcd.: C, 80.73; H, 9.03. Found: C, 81.06; H,

Example 13.2-Furylmethyl 2-Methyl-3-ethyl-4-phenyl- 4-cyclohexenecarboxylate This ester is prepared from the cyclohexenyl acid chloride and furfuryl alcohol, following the procedure of Example 2. Chromatography affords a crystalline ester which is purified by recrystallization from ether to afford the 1-furylmethyl ester, white prisms of m.p. 8384.

Mmax; 5.80, 8.29, 8.56, 8.62, 11.9-12.0, 13.11, 13.41,

14.20 (KBr).

Empirical Formula: C H O Calcd.: C, 77.75; H, 7.46. Found: C, 78.02; H, 7.67.

Example 14.-p-Carbomethoxyphenyl 2-Methyl-3-ethyl-4- phenyl-4-cyclohexenecarboxylate This ester is prepared from the cyclohexenyl acid chloride and methyl p-hydroxybenzoate, following the procedure of Example 2. Chromatography, followed by recrystallization from ether gives the ester as white granules of m.pt. 105-106.

Mmaxa 5.70, 5.86, 7.78, 8.39, 8.80, 9.00, 11.79, 13.08,

Empirical Formula: C H O Calcd.: C, 76.16; H, 6.93. Found: C,76.08; H, 6.91.

Example 15 .2- (N-Piperidino )ethyl 2-Methyl-3-ethyl-4- phenyl-4-cyclohexenecarboxylate This ester is prepared from the cyclohexenyl acid chloride and N-(B-hydroxyethyl)piperidine, following the procedure of Example 2, but omitting acid washes which are normally used to remove pyridine. Pyridine is, in this example, removed by evaporation. Chromatography, followed by distillation, affords the ester as a yellow oil of b.pt. -170 at 0.001 mm.

Mmax; 5.78, 8.30, 8.61, 11.88, 13.20, 14.29,:t. Empirical Formula: C H O N. Calcd.: C, 77.70; H, 9.36. Found: C, 77.71; H, 9.10.

Example 16.-Decyl 2-Methy1-3-ethyl-4- (p-cyclopentoxyphenyl -3-cyclohexenecarb oxylate Ahmax; 5.75, 8.03, 8.61, 10.05, 12.08;t.

Empirical Formula: C H O =469.7.

Anal.Calcd.: C, 79.43; H, 10.32. Found: C, 79.08; H,

Example 17.--Decyl 2-Methyl-3-ethyl-4-(p-hydroxyphenyl)-3- and 4-cyclohexenecarboxylate A. 1.0 g. of 2-methyl 3 ethyl 4 (p-acetoxyphenyl)- 3- and 4-cyclohexenecarboxylic acid prepared as disclosed in U.S. Application No. 723,614 (mixture of isomers) is converted to the acid chloride as described in Example 2. The undistilled acid chloride is converted to the decyl ester with n-decyl alcohol and purified by chromatography, as also described in Example 2, followed by distillation to give 0.6 g. of decyl 2-methyl-3-ethyl-4(p-acetoxyphenyl)- 3 and 4-cyclohexenecarboxylate:

err-,0 m-Q-Qo 020101121 2H5 CH3 This is a pale yellow viscous oil of b. pt. 170-180 at 0.001 mm. The NMR spectrum shows an approximate 1:1 mixture of the A and A isomers.

Anal.-Calcd. for C H O C, 75.97; H, 9.56. Found:

B. The distilled mixture of isomers described in A (previous page) is refluxed for eight minutes in 30 ml. of methanol containing 4 ml. of water and 0.8 g. of potassium bicarbonate. The resulting clear solution is evaporated to remove methanol and the oily product is extracted with ether. The ether solution is dried and concentrated, and the residue is distilled to atford 0.5 g. of a very viscous pale yellow oil, b. pt. 185-195" at 0.001 mm. NMR shows this to be an approximate 1:1 mixture of decyl 2-methyl-3-ethyl 4 (p-hydroxyphenyl)-3-cyclohexenecarboxylate and decyl 2-methy1 3 ethyl-4-(p-hydroxyphenyl) -4-cyclohexenecarboxylate.

Empirical Formula: C H O ==400.6. Anal.-Calcd.: C, 77.95, H, 10.07. Found: C, 76.96; H,

Example 18.Decyl 2-Methy1-3-ethyl-4- (m-tolyl) -3- cyclohexenecarboxylate A mixture of 0.5 g. of 2-methyl-3-ethyl-4-(m-tolyl)-3- cyclohexenecarboxylic acid (Example 6 of U.S. Application No. 747,075 and 5 ml. of thionyl chloride is refluxed for 15 minutes and then diluted with ml. of toluene and evaporated under vacuum to a viscous oil of the acid chloride. The latter is treated with a solution of 1 ml. of decyl alcohol in 5 ml. of pyridine and this mixture is heated at 95 for 20 minutes and then diluted with hexane and washed with dilute hydrochloric acid. The hexane solution is dried and evaporated and the residual crude ester is chromatographed on alumina. Elution with benzene+hexane gives the ester, which is distilled to afford 0.4 g. of decyl 2-methyl 3 ethyl-4-(m-tolyl)-3-cyclohexenecarboxylate, a viscous pale yellow oil of b. pt. 155- 160 at 0.001 mm.

Mmax; 5.77, 8.63, 9.94, 12.78, 14.16 1.

Empirical Formula. C H O =3986 Anal.Calcd.: C, 81.35; H, 10.62. Found: C, 81.24; H,

Example 19.-2-Methyl-2-butenyl 2-Methyl-3ethyl-4- (p-anisyl)-3-cyclohexenecarboxylate This ester is prepared as detailed in Example 18, starting with 0.7 g. of 2-methyl 3 ethyl 4 (p-anisyl)-3- cyclohexenecarboxylic acid (disclosed in U.S. Pat. 2,582,- 253) and reacting the intermediate acid chloride with tiglyl alcohol (2-rnethyl-2-buten-l-ol). Isolation and purification are performed as described in Example 18, and the ester is distilled to afiford the product as a pale yellow oil (0.55 g.) of b. pt. 145-150 at 0.001 mm.

Mmax; 5.75, 8.01, 8.62, 9.65, 9.98, 12.05

Empirical Formula: C H O =342.5.

Anal.--Calcd.: C, 77.15; H, 8.83. Found: C, 77.33; H,

8 Example 20.2-Furylmethyl 2-Methyl-3-ethyl-4-(oanisyl) -4-cyclohexenecarboxylate This ester is prepared according to the procedure detailed in Example 18 starting with 0.7 g. of 2-methyl-3- ethyl-4-(o-anisyl) 4 cyclohexenecarboxylic acid prepared as disclosed in U.S. Application No. 747,075 and reacting the intermediate acid chloride with furfuryl alcohol. Isolation and purification are performed as in Example 18, yielding a solid ester which is then recrystallized from hexane to afford the product as white prisms which melt at 81-82". A weak hydroxyl band in the infrared spectrum, as well as the analytical values, support a formulation with partial molecule of water in the crystal.

Mmax: 3.15, 5.77, 8.62, 10.00, 10.27, 10.80, 11.69-11.83,

12.18, 1304,1322 (KBr).

Empirical Formula: C H /1.H O-=358.9.

Calcd.: C, 73.62; H, 7.44. Found: C, 73.35; H, 7.33.

Example 21.-Benzyl 2-Methyl-3-ethyl-4-(p-cyclopentoxyphenyl) -3-cyclohexenecarboxylate This ester is prepared according to the procedure detailed in Example 18, starting with 0.7 g. of 2-methyl-3- ethyl -4-(p-cyclopentoxyphenyl)-3-cyclohexenecarboxylic acid prepared as disclosed in U.S. Application No. 662,310, and reacting the intermediate acid chloride with benzyl alcohol. Isolation and purification are performed as in Example 18, and the ester is distilled to afford the product as a viscous oil (0.4 g.) of b. pt. -200 at 0.001 mm.

A). max.: 5.75, 8.03, 8.63, 9.94, 10.03, 12.07, 13.30, 13.61,

Empirical Formula: C H O 418.6.

Calcd.: C, 80.34; H, 8.19. Found: C, 80.45; H, 8.34.

Example 22 .-Dodecyl 2-Methyl-3-ethyl-4- (m-chlorophenyl)-4-eyclohexcnecarboxylate This ester is prepared from the cyclohexenyl acid chloride in which the 4-phenyl group is m-chloro substituted (prepared as disclosed in U.S. Application No. 747,075) and n-dodecanol, following the procedure of Example 2. Chromatography on alumina aifords the crude ester free of the fatty alcohol and distillation gives the ester as a colorless oil of b.pt. -200/.001 mm.

M max.: 5.78, 8.60, 10.01, 11.31, 11.88, 12.78, 13.70,

Empirical Formula: C H O Cl.

Calcd.: C, 75.21; H, 9.69. Found: C, 75.28; H, 9.63.

Example 23.-Decyl 2-Methyl-3-ethy1-4- (p-acetoxyphenyl)-3-cyclohexenecarboxylate The crude acid chloride is prepared as described in Example 2 from 0.6 g. of 2-methyl-3-ethyl-4-(p-acetoxyphenyl)-3-cyclohexenecarboxylic acid (prepared as disclosed in U.S. Application No. 723,614) and 5 ml. of thionyl chloride (this follows the general procedure). This crude acid chloride is then reacted with decyl alcohol in pyridine again following the procedure of Example 2. Chromatography on alumina affords crude ester and distillation gives the desired ester as a pale yellow oil of b. pt. 180-190/.001 mm.

A). max.: 5.67, 5.78, 8.33, 8.60, 9.82, 10.97, 11.80, 12.52;. Empirical Formula: (2 E 0, 442.6. Calcd.: C, 75.97; H, 9.56. Found: C, 75.84; H, 9.69.

Example 24.B-Methoxyethyl 2-Methyl-3-ethyl-4- phenyl-4-cyclohexenecarboxylate This ester is prepared from the A -cyclohexenyl acid chloride and ethylene glycol monomethyl ester, following the procedure of Example 2 Chromatography on alumina affords crude ester and distillation gives the desired ester as a pale yellow oil of b. pt. 130135/.001 mm.

A). max.: 5.78, 8.30, 8.60, 8.81, 9.57, 11.57 11.88, 13.22,

The parenteral anti-littering properties of the compounds are measured by administering to adult female rats of Wistar-derived strain a single subcutaneous injection of the test material in sesame oil. Controls receive sesame oil vehicle only. Ordinarily twenty animals are as- Empirical Formula: C H O 302.4. signed to each g p Calcd" 75'46; Found: 7140; Both groups are cohabitated with adult male rats in the Example 25.Carbethoxymethyl 2-Methyl-3-ethyl-4- ratio of 3 males per females starting on the day of phenyl-4-cycl0hexenecarboxylate treatment. Rats are examined twice weekly for gross signs This ester is prepared from the A -cyclohexenyl acid of Pregnancy Gravld ammals are removed e allevfred chloride and ethyl glycolate, following the procedure of to dehver so that a count of young and eendmon Example 2. Chromatography on alumina afiords crude e be ,reeerded' The e Interval between e ester and distillation gives the desired ester as a colorless mmlstretlen (and eehaeltenen) and eeneepeen 1s ealeu oil of PL 150 155/ O01 mm. lated for each group usmg an average gestation length of 21 days. M max-3 5-68, 5-73, 8-19, 834, 9-31, ,Cohabitation is continued for 90 days or until 80% of Q 13-20, 14-24% the females become pregnant, whichever occurs sooner. Empll'lcal Formula! C20H26O4'= 330.4. The minimum dosage in mg./kg. body weight required Calcd.: C, 72.70; H, 7.93. Found: C, 72.77; H, 8-09- to prevent littering in the rats for various compounds, While the preparation of only some of the compounds 20 the preparatlon of whlch was speclfically described 1n the of this invention have been specifically described, one examples 13 Set out In T e The f efieet of e skilled in the art should be able to prepare the remainder of the eempounds on httenng at venous dosage levels 15 of the compounds following the general techniques set Set m Table f fl While the determination of the antilrttering effect of AS mentioned Previously, the compounds of this a compound 1s mportant in that 1t shows 'whether or not vention exhibit anti-littering eifects when given orally or a eempound suppress feproeuetlon 1t e e parenterally and are estrogenic agents to varying degrees. Pomt the Preelse manner whleh reproduetlen 15 Estrogenic eifects are measured against the estrogenic e has been t l that the of efiects of estradiol as a standard. In carrying out the test, the ,leveneon are also antllygmlc e 15 female rats of Wistar-derived strain are bilaterally fertlhzed ovum and antlzygoflc agent one whleh ovariectomized under light ether anesthesia. About a destroys F zygote pner to e m the i Week following surgery all animals are given a priming Si specific form of zygote destruetlen IS the lysmg of dose of 2-10 1g. etstradiol-17B by subcutaneous injection t e zygote and vaginal smears are taken on each of the next two to determme Whether or not a 18 days. Animals which do not show vaginal cornification anezygeec edult male and rats are eehablteted are rested a week and reprimed. Rats which respond posisperm found m vagme' Fellewmg the Pres tively to the priming injection are rested a Week and then P of i g female g g dosfid P i Succesgiven a single subcutaneous injection of the test material ewe days with t e eempeun an on t e me day aeter in sesame oil. Vaginal smears are taken daily to assess 40 the Presence of Sperm noted the rats are autepsled the duration of estrogenic response (vaginal comifica and the uteri are examined for thepresence of conceptuses. tion) in each animal as opposed to the vaginal cornifica Lack of conceptuses indicates antizygotlc effect. A control hon induced by the priming The results tabulated in group of rats is similarly treated except that there is no Table I, for certain of the compounds prepared according dosmg Wlth the compound under testto the examples hereinbefore set out show that the com- Table I tabulates C rt compounds) the pounds of this invention have substantial estrogenic mum effective dosage of said compounds needed to obtain activity. an antizygotic efiect.

TABLE I If B 0-0 0' Pharmacological activity it Antilitterlng Antl- R R A zygotic 3 Estrogenic 4 Oral Parenteral Example 1 1 H CHOHOHOH2OH 4 10 g. 2XEE 10 pg. Inact. 5 mg.

2 H 7 4 500 g. 1 500 g. mg. (S-C) 3.-:.:.:.:-.r.:.:.:.:-.:-:....:-:.:.:. H CH(C5H5)7 4 20 pg. 2/5XEE 25pg. 2.5 mg.

4...'..-.: H CHI-CH1 4 ZXEE 5pg. 1.0 mg.

CHrCHg 5.....:::..::::::.:.:. H C10Hz1 4 XEE 25pg. 1.0 mg.

1 1 1 2 TABLE IContinued Pharmacological activity 1 Antilittering Anti- R R A zygotic Estrogenic Oral Parenteral Example: 1

6 H 4 IXEE 10 pg. 1.0 mg.

CH3 CIH5 7 H 4 m g 4XEE 25ug. 1.0 mg.

8 H 4 6/10XEE pg. 1.0 mg;

9 H -CH,O.H 4 25 g. IXEE 10 g. 1.0 mg.

10 H CH 4 4/100XEE 100 pg. 2.5 mg.

-CH(CH:)iuCHa l1 H -CH;$=CHCH; 3 ZXEE 50.25 mg.

12 H -CH;(]J=CHCH3 4 2XEE 5ug. 2.0 mg. CH:

13 H n 4 10 pg. 1.3XEE Spg. 2.0 mg.

--CH2-L J 14 H A IXEE 1.0 mg.

15 H 4 8/10XEE 2.5 mg.

CH1CH:-,N

i6 I o --CmH;1 3 0.6XEE pg.

173 p-HO- C1cH;1 3 LZXEE 5pg. 1.0 mg.

18 m-CH; -CmH; 3 1/10XEE 100 pg.

19 p-CHaO- CIH; 3 1.7XEE 2.5 pg. 0.5 mg.

-CH:C=CHCH3 20 O-CHz-O- H 4 OJXEE 100 pg. =L

21 3 IXEE 5 22 m-Cl C1:H25 4 5/1000XEE 1.0 mg.

23 H -Cio ai 3 2.0 mg.

p-GHzC-O- 24 H GH:CH;OCH; 4 LSXEE 2.0mg.

25 H --CH:COzCzHa 4 1.5XEE 2.0 mg.

Haxyl I-carboxylafn 4 0.5XEE 10 pg. 2.5 mg. Octyl 1-carhoxylate.- 4 1.3XEE 10 Pg. 2.5 mg.

l Example in which compound appears.

1 Pharmacological activity entries are all (female rat) data.

I Antizygotic: Oral administration; gJkg Estrogenic: Oral administration; potency is times estradiol as standard.

Antilittering oral: Administered in the diet or intregastrically 1 This is the l-adamantyl group.

Number litters/ Mean value day number rats pregnancy occurred Compound of example:

mum

US. Cl. X.R.

260293.81, 347.4, 473 R, 473 S, 479 R, 515 R, 515 A; 424267, 285, 308

3. 2-Methy1-2-butenyl 2-methyl-3-ethyl-4-phenyl-4-cyclohexenecarboxylate.

References Cited UNITED STATES PATENTS 3,344,147 9/1967 Mebane 260-469 OTHER REFERENCES Chemical Abstracts, vol. 68, p. 86852t (1968).

LORRAINE A. WEINBERGER, Primary Examiner P. J. I-IAGAN, Assistant Examiner er (Exally or in small doses compared to the octyl and hexyl 50 esters of US. Pat. 3,344,147. The secondary alkyl esters 1 No pregnancies.

From Table I it can be seen that the alkenyl esters From Table II it can be seen that the 2-adamanty1 esters (Example 7) have long acting elfects when admin- What is claimed is: 1. 2-Nonadecyl 2-methyl-3-ethyl-4-phenyl-4eyclohexr enecarboxylate.

2. 2-Methyl-2-butenyl 2-methyl-3-ethyl-4pheny1-3-cyclohexenecarboxylate.

Octyl l-carboxylatmu-ne- (Examples 11 and 12) and the cyclopentyl est ample 4) are active when administered parenter orally (Example 10) have high oral activity despite very 10w estrogenicity. The l-adamantyl esters (Example 2) also exhibit oral and parenteral activity despite very low estrogenicity.

istered orally or parenterally compared with the octyl ester of US. Pat. 3,344,147. 

